Retroviral vectors have been constructed that express one or more of the following gene products: sCD4 (or it's derivatives), transdominant rev mutants, and an HIV inducible alpha-interferon or diphtheria toxin. The goal of this work is to engineer human hematopoietic cells such that they manifest anti-HIV activity and thus may prevent HIV infection or decrease viral replication. Initial work has concentrated on construct retroviral vectors that produce a secreted form of the helper/inducer T-cell antigen, CD4 (sCD4). Analysis of this system has been carried out through the in vivo animal testing stage. We have demonstrated that sCD4 transduced primary human lymphocytes can be directly protected from HIV infection in vitro. We have further documented protection of human lymphocytes from infection by HIV in the Hu-PBL-SCID mouse AIDS animal model.